Ovarian hormone deficiency is one of the main risk factors for osteoporosis and bone fractures in women, and these risks can be mitigated by menopausal hormone therapy. Recent evidence suggests that ...gut microbiota may link changes in estrogen levels and bone metabolism. This study was conducted to investigate the potential relationship between hormonal and bone changes induced by oophorectomy and subsequent hormonal therapy and shifts in gut microbiota composition.
We collected 159 stool and blood samples in several intervals from 58 women, who underwent bilateral oophorectomy. Changes in fecal microbiota were assessed in paired samples collected from each woman before and after oophorectomy or the start of hormone therapy. Bacterial composition was determined by sequencing the 16S rRNA gene on Illumina MiSeq. Blood levels of estradiol, FSH, biomarkers of bone metabolism, and indices of low-grade inflammation were measured using laboratory analytical systems and commercial ELISA. Areal bone mineral density (BMD) of the lumbar spine, proximal femur, and femur neck was measured using dual-energy X-ray absorptiometry.
We found no significant changes in gut microbiota composition 6 months after oophorectomy, despite major changes in hormone levels, BMD, and bone metabolism. A small decrease in bacterial diversity was apparent 18 months after surgery in taxonomy-aware metrics. Hormonal therapy after oophorectomy prevented bone loss but only marginally affected gut microbiota. There were no significant differences in β-diversity related to hormonal status, although several microbes (e.g.,
) followed estrogen levels. Body mass index (BMI) was the most significantly associated with microbiota variance. Microbiota was not a suitable predictive factor for the state of bone metabolism.
We conclude that neither the loss of estrogens due to oophorectomy nor their gain due to subsequent hormonal therapy is associated with a specific gut microbiota signature. Sources of variability in microbiota composition are more related to interindividual differences than hormonal status.
Objective
Although calcitriol is essential for bone healing, its serum concentrations are low after hip surgery, and they continue to decline during bone healing. This study aimed to test the ...hypothesis of an association of changes in calcitriol production with the status of fibroblast growth factor 23 (FGF23) and iron deficiency after elective hip replacement for coxarthrosis.
Methods
In this prospective study, we measured the biomarkers of 17 patients undergoing elective hip replacement on admission, on the first day after surgery, and at the regular check-up after 48 ± 8 days. The serum concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, transferrin, ferritin, parathyroid hormone, intact plasma FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) were determined.
Results
In our patients who underwent elective hip replacement, significant correlations existed between the percent change in the conversion rate of 25(OH)D to 1,25(OH)
2
D, plasma intact to C-terminal FGF23 ratio, and serum iron.
Conclusions
The production of calcitriol is compromised after elective hip replacement surgery, leading to reduced levels of active vitamin D in the serum. Significant correlations between the percent change in the conversion rate of 25(OH)D to 1,25(OH)
2
D, plasma intact to C-terminal FGF23 ratio, and serum iron on the first day as well as 7 weeks after surgery could inspire future studies to determine whether and how calcitriol deficiency should be corrected, especially in fracture cases.
Summary
FRAX
®
calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in ...postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX
®
-defined MOF compared with those treated with risedronate.
Introduction
The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX
®
-defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures.
Methods
In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 μg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX
®
-defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval.
Results
After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX
®
-defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23–0.68;
p
= 0.001). Clinical vertebral and radius fractures were the most frequent FRAX
®
-defined MOF sites. The largest difference in incidence rates of both FRAX
®
-defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed.
Conclusion
In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX
®
-defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment.
Clinical trial information
ClinicalTrials.gov
Identifier: NCT01709110
EudraCT Number: 2012-000123-41
Osteoporosis is associated with an impaired balance between bone resorption and formation, which in turn leads to bone loss and fractures. Many recent studies have underlined the regulatory role of ...microRNAs (miRNAs) in bone remodeling processes and their potential as biomarkers of osteoporosis. The purpose of this study was to prospectively examine the association of circulating miRNAs and bone biomarkers with estrogen status in women before and after oophorectomy, as well as in oophorectomized women on estrogen therapy.
In this prospective study, we included 11 women before oophorectomy and hysterectomy and at 201 ± 24 days after the surgery. Another 11 women were evaluated 508 ± 127 days after oophorectomy and hysterectomy and after an additional 203 ± 71 days of estradiol treatment. Serum miRNAs were profiled by sequencing. Estrogen status and biomarkers of bone metabolism were quantified. Bone mineral density was assessed in the lumbar spine.
Our analysis revealed 17 miRNAs associated with estrogen levels. Of those miRNAs that were upregulated with estrogen deficiency and downregulated after estrogen therapy, miR-422a correlated with serum beta-carboxy-terminal type I collagen crosslinks (β-CTX) and procollagen 1 N-terminal propeptide (P1NP); and miR-1278 correlated with serum β-CTX, P1NP, osteocalcin, sclerostin, and Dickkopf-1(Dkk1). In contrast, we found an inverse association of miR-24-1-5p with estrogen status and a negative correlation with serum β-CTX, P1NP, osteoprotegerin, and sclerostin levels.
The reported miRNAs associated with estrogen status and bone metabolism could be potential biomarkers of bone pathophysiology and would facilitate studies on the prevention of postmenopausal osteoporosis. Our findings require validation in an extended cohort.
Objective
To assess the decrease in serum calcitriol concentrations after hip fracture.
Methods
Serum concentrations of calcitriol, 25(OH)D, parathyroid hormone (PTH), directly measured free 25(OH)D, ...and indices of bone formation were measured in elderly patients with hip fracture (HF) and patients with elective hip replacement (EHR) at admission and after 7 weeks.
Results
A total of 45 patients with HF and 17 patients with EHR completed this prospective study. Baseline serum calcitriol levels were ≤ 60 pmol/l in 26% of the HF patients. After 7 weeks, they significantly decreased (
p
< 0.001). In patients with EHR, serum calcitriol was within the reference range in all but one patient and did not change during the 7-week recovery phase. Seven weeks after HF, a significant positive relationship was observed between the change in calcitriol and serum 25(OH)D concentration (
r
= 0.385,
p
= 0.009) and free 25(OH)D (
r
= 0.296,
p
= 0.048), and a decrease in calcitriol during recovery was associated with a decrease in serum PTH (
p
= 0.038). Seven weeks after HF, changes in both serum PTH and serum 25(OH)D concentrations contributed to the prediction of changes in serum calcitriol (
R
2
= 0.190,
p
= 0.012).
Conclusions
Unlike patients with EHR, subjects with HF had low serum 25(OH)D and low free 25(OH)D concentrations at admission, while their serum 1,25D levels were relatively elevated. Decreases in circulating calcitriol levels in the 7 weeks following hip surgery were associated with a resolution of secondary hyperparathyroidism and low availability of free 25(OH)D.
Summary
A 12-month morning teriparatide (TPTD) administration resulted in a larger increase in the lumbar spine bone mineral density (BMD) than the evening application. The results indicate that the ...response of bone cells to teriparatide treatment depends on dosing time.
Introduction
The aim of this study was to assess the long-term effects of the morning vs. the evening teriparatide administration on BMD and bone turnover markers (BTMs) in postmenopausal osteoporosis.
Methods
Fifty women with established postmenopausal osteoporosis were randomized to 12-month treatment with 20 μg of TPTD, administered daily in the morning or in the evening. The BMD and serum concentrations of C-terminal telopeptide of type I collagen, N-terminal propeptide of type I procollagen (PINP), and tartrate-resistant acid phosphatase isoform 5b (TRAP 5b) were measured at baseline, after 6 and 12 months. General linear model-repeated measurements were used to analyze the data.
Results
After 12 months, the lumbar spine BMD grew markedly (
p
< 0.001) with a significantly greater increase in the morning arm compared to the evening arm (9.1% vs. 4.8%, respectively,
p
< 0.05). The BMD at the distal radius significantly decreased (
p
< 0.001), with no differences between the arms. The BMD at proximal femur did not change significantly. After 6 months, the BTMs were significantly increased compared with baseline (
p
< 0.001). The increases in the evening arm vs. the morning arm, however, were more pronounced in PINP (+358% vs. +215%, respectively) and in TRAP 5b (+70% vs. +37%, respectively) (both
p
< 0.05).
Conclusion
12-month morning administration of TPTD resulted in a larger increase in the lumbar spine BMD than the evening application. The timing of TPTD administration may be important for its efficacy.
Vertebral fractures are associated with back pain and disability. There are, however, few prospective data looking at back pain and disability following identification of radiographic vertebral ...fracture. The aim of this analysis was to determine the impact of radiographically identified vertebral fracture on the subsequent occurrence of back pain and disability. Women aged 50 years and over were recruited from population registers in 18 European centers for participation in the European Prospective Osteoporosis Study. Participants completed an interviewer-administered questionnaire which included questions about back pain in the past year and various activities of daily living, and they had lateral spine radiographs performed. Participants in these centers were followed prospectively and had repeat spine radiographs performed a mean of 3.7 years later. In addition they completed a questionnaire with the same baseline questions concerning back pain and activities of daily living. The presence of prevalent and incident vertebral fracture was defined using established morphometric criteria. The data were analyzed using logistic regression with back pain or disability (present or absent) at follow-up as the outcome variable with adjustment made for the baseline value of the variable. The study included 2,260 women, mean age 62.2 years. The mean time between baseline and follow-up survey was 5.0 years. Two hundred and forty participants had prevalent fractures at the baseline survey, and 85 developed incident fractures during follow-up. After adjustment for age, center, and the baseline level of disability, compared with those without baseline prevalent fracture, those with a prevalent fracture (odds ratio OR = 1.4; 95% confidence interval CI 1.0 to 2.0) or an incident fracture (OR = 1.7; 95% CI, 0.9 to 3.2) were more likely to report disability at follow-up, though the confidence intervals embraced unity. Those with both a prevalent and incident fracture, however, were significantly more likely to report disability at follow-up (OR = 3.1; 95% CI, 1.4 to 7.0). After adjustment for age, center, and frequency of back pain at baseline, compared with those without baseline vertebral fracture, those with a prevalent fracture were no more likely to report back pain at follow-up (OR = 1.2; 95% CI, 0.8 to 1.7). There was a small increased risk among those with a preexisting fracture who had sustained an incident fracture during follow-up (OR = 1.6; 95% CI, 0.6 to 4.1) though the confidence intervals embraced unity. In conclusion, although there was no significant increase in the level of back pain an average of 5 years following identification of radiographic vertebral fracture, women who suffered a further fracture during follow-up experienced substantial levels of disability with impairment in key physical functions of independent living.
Abstract Marked suppression of bone turnover by bisphosphonates is associated with increased bone microdamage accumulation in animal models. The purpose of this study was to test the hypothesis that ...long-term treatment with alendronate (ALN) results in accumulation of microdamage in bone in women after menopause. Sixty-six postmenopausal women with osteoporosis (mean age of 68.0 years and mean BMD T -score of − 1.7 at total hip and − 2.8 at lumbar spine; 62% with prevalent fractures) were evaluated in this cross-sectional analysis. Thirty-eight had been treated previously with ALN (10 mg/day or 70 mg/week for a mean duration of 63.6 months) while twenty-eight were treatment naive (TN). Without adjustments, crack surface density (Cr.S.Dn) and crack density (Cr.Dn) were not different between ALN and TN patients. After adjustment for potential confounders (age, prevalent fractures, femoral neck BMD, activation frequency and center), Cr.Dn was elevated in ALN patients ( P = 0.028 and P = 0.069 for Cr.S.Dn). In ALN patients only, lower femoral neck BMD (Cr.S.Dn, r = − 0.58, P = 0.003; Cr.Dn, r = − 0.54, P = 0.005) and increased age (Cr.S.Dn, r = 0.43, P = 0.03; Cr.Dn, r = 0.43, P = 0.03) were associated with microdamage accumulation. Among potential confounders, femoral neck BMD was the only independent predictor for these correlations ( P = 0.04 for Cr.Dn and P = 0.03 for Cr.S.Dn). We conclude that increased microdamage accumulation may occur in low BMD patients treated with alendronate.
Raloxifene, a selective estrogen receptor modulator approved for the prevention and treatment of postmenopausal osteoporosis, has shown a significant reduction in breast cancer incidence after 3 ...years in this placebo-controlled, randomized clinical trial in postmenopausal women with osteoporosis. This article includes results from an additional annual mammogram at 4 years and represents 3,004 additional patient-years of follow-up in this trial. Breast cancers were ascertained through annual screening mammograms and adjudicated by an independent oncology review board. A total of 7,705 women were enrolled in the 4-year trial; 2,576 received placebo, 2,557 raloxifene 60 mg/day, and 2,572 raloxifene 120 mg/day. Women were a mean of 66.5-years old at trial entry, 19 years postmenopause, and osteoporotic (low bone mineral density and/or prevalent vertebral fractures). As of 1 November 1999, 61 invasive breast cancers had been reported and were confirmed by the adjudication board, resulting in a 72% risk reduction with raloxifene (relative risk (RR) 0.28, 95% confidence interval (CI) 0.17, 0.46). These data indicate that 93 osteoporotic women would need to be treated with raloxifene for 4 years to prevent one case of invasive breast cancer. Raloxifene reduced the risk of estrogen receptor-positive invasive breast cancer by 84% (RR 0.16, 95% CI 0.09, 0.30). Raloxifene was generally safe and well-tolerated, however, thromboembolic disease occurred more frequently with raloxifene compared with placebo (p=0.003). We conclude that raloxifene continues to reduce the risk of breast cancer in women with osteoporosis after 4 years of treatment, through prevention of new cancers or suppression of subclinical tumors, or both. Additional randomized clinical trials continue to evaluate this effect in postmenopausal women with osteoporosis, at risk for cardiovascular disease, and at high risk for breast cancer.
Summary The level of increased bone formation after 24 months of treatment with teriparatide (rhPTH (1-34), TPTD) is similar in patients who were either treatment-naïve (TN) or had lower bone ...turnover initially due to previous alendronate (ALN) therapy. Introduction Bone anabolic effects of TPTD in postmenopausal women with osteoporosis may be blunted during the initial phase after switching from ALN to TPTD. To explore the long-term implications, we examined histomorphometric and biochemical markers of bone turnover of patients on TPTD therapy after long-term ALN treatment. Methods Paired biopsies were obtained after tetracycline double labeling at baseline and after 24 months of TPTD treatment from 29 ALN-pretreated (64.5 ± 16.4 months) and 16 TN patients. Biochemical markers were measured at baseline, during the treatment, or at study end. Results Compared with the baseline, after 24-month TPTD, activation frequency (Ac.F.) and osteoid surface (OS) increased in both groups: 0.11-0.34 cycles per year, 3.96-9.8% in the ALN-pretreated group and 0.19-0.33 cycles per year, 6.2-11.3% (p < 0.05) in the TN group, respectively. Biochemical and histomorphometric markers correlated positively both at baseline and endpoint. Serum amino terminal propeptide of type I procollagen (PINP) correlated with Ac.F. (r = 0.57, p < 0.001 and r = 0.48, p < 0.01) and OS (r = 0.51, p < 0.01 and r = 0.56, p < 0.01) at baseline and endpoint, respectively. Following 3 months of treatment, increases in biochemical markers like PINP predicted the increase in Ac.F. (r = 0.52, p < 0.01) and OS (r = 0.54, p < 0.01) after 24 months. Conclusions The increased level of formation is similar in patients who were either TN or had lower bone turnover initially due to previous ALN therapy. Elevated bone formation in postmenopausal women with osteoporosis was sustained over a 24-month period by TPTD. Biochemical markers of bone formation are a good surrogate for the assessment of TPTD effects.
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